Cancer therapies comprise a wide range of therapeutic approaches, including surgery, radiation, and chemotherapy. While the often complementary approaches allow a broad selection to be available to the medical practitioner to treat the cancer, existing therapeutics suffer from a number of disadvantages, such as a lack of selectivity of targeting cancer cells over normal, healthy cells, and the development of resistance by the cancer to the treatment.
Recent approaches to treating cancer based on targeted therapeutics, such as antibodies, have led to chemotherapeutic regimens with fewer side effects as compared to non-targeted therapies such as radiation treatment. One effective approach for enhancing the anti-tumor-potency of antibodies involves linking cytotoxic drugs or toxins to monoclonal antibodies that are capable of being internalized by a target cell. These agents are termed antibody-drug conjugates (ADCs). Upon administration to a patient, ADCs bind to target cells via their antibody portions and become internalized, allowing the drugs or toxins to exert their effect (see, e.g., U.S. Patent Appl. Publ. Nos. US2005/0180972 and US2005/0123536).
Prolactin receptor (PRLR) is a single membrane-spanning class 1 cytokine receptor that is homologous to receptors for members of the cytokine superfamily, such as the receptors for IL2, IL3, IL4, IL6, IL7, erythropoietin, and GM-CSF. PRLR is involved in multiple biological functions, including cell growth, differentiation, development, lactation and reproduction. It has no intrinsic tyrosine kinase activity; however, ligand binding has been shown to lead to receptor dimerization, cross-phosphorylation of Jak2 and downstream signaling. Human prolactin receptor cDNA was originally isolated from hepatoma and breast cancer libraries (Boutin et al., Molec. Endocr. 3: 1455-1461, 1989). The nucleotide sequence predicted a mature protein of 598 amino acids with a much longer cytoplasmic domain than the rat liver PRL receptor. The prolactin receptor gene resides in the same chromosomal region as the growth hormone receptor gene, which has been mapped to 5;13-p 12 (Arden, K. C. et al. Cytogenet. Cell Gene 53: 161-165, 1990; Arden, K. C. et al., (Abstract) AM. J. Hum. Genet. 45 (suppl.): A129 only, 1989). Growth hormone also binds to the prolactin receptor and activates the receptor.
PRLR exists in a number of different isoforms that differ in the length of their cytoplasmic domains. Four PRLR mRNA isoforms (L, I, S1a, and S1b) have been identified in human subcutaneous abdominal adipose tissue and breast adipose tissue (Ling, C. et al., J. Clin. Endocr. Metab. 88: 1804-1808, 2003). In addition, expression of both L-PRLR and I-PRLR has been detected in human subcutaneous abdominal adipose tissue and breast adipose tissue using immunoblot analysis. Recent reports have suggested PRLR is expressed and activated in human breast cancer and prostate cancer tissues (Li et al., Cancer Res., 64:4774-4782, 2004; Gill et al., J Clin Pathol., 54:956-960, 2001; Touraine et al., J Clin Endocrinol Metab., 83:667-674, 1998). Reportedly, Stat5 activation and PRLR expression is associated with high histological grade in 54% of prostate cancer specimens (Li et al., supra). Other reports suggest primary breast cancer specimens are responsive to PRL in colony formation assays, and that plasma PRL concentrations correlate with breast cancer risk (Tworoger et al., Cancer Res., 64:6814-6819, 2004; Tworoger et al., Cancer Res., 66:2476-2482, 2006). In another report, PRL transgenic mice developed malignant mammary carcinomas or prostate hyperplasia (Wennbo et al., J Clin Invest., 100:2744-2751, 1997; Wennbo et al., Endocrinology, 138:4410-4415, 1997). Blockade of PRLR signaling may be a means for treating breast and prostate cancer. (See, e.g., Damiano and Wasserman, April 2013, Clin. Cancer Res. 19(7):1644-1650).
Thus, there is a need in the art for novel PRLR antagonists for the treatment of cancer and other disorders associated with detrimental PRLR activity.